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Review
. 2021 Jul 8:12:717540.
doi: 10.3389/fimmu.2021.717540. eCollection 2021.

The Effects of Interferons on Allogeneic T Cell Response in GVHD: The Multifaced Biology and Epigenetic Regulations

Chenchen Zhao  1 , Yi Zhang  2 , Hong Zheng  1
Affiliations
Review

The Effects of Interferons on Allogeneic T Cell Response in GVHD: The Multifaced Biology and Epigenetic Regulations

Chenchen Zhao et al. Front Immunol. .

"V体育2025版" Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. This beneficial effect is derived mainly from graft-versus-leukemia (GVL) effects mediated by alloreactive T cells. However, these alloreactive T cells can also induce graft-versus-host disease (GVHD), a life-threatening complication after allo-HSCT. Significant progress has been made in the dissociation of GVL effects from GVHD by modulating alloreactive T cell immunity VSports手机版. However, many factors may influence alloreactive T cell responses in the host undergoing allo-HSCT, including the interaction of alloreactive T cells with both donor and recipient hematopoietic cells and host non-hematopoietic tissues, cytokines, chemokines and inflammatory mediators. Interferons (IFNs), including type I IFNs and IFN-γ, primarily produced by monocytes, dendritic cells and T cells, play essential roles in regulating alloreactive T cell differentiation and function. Many studies have shown pleiotropic effects of IFNs on allogeneic T cell responses during GVH reaction. Epigenetic mechanisms, such as DNA methylation and histone modifications, are important to regulate IFNs' production and function during GVHD. In this review, we discuss recent findings from preclinical models and clinical studies that characterize T cell responses regulated by IFNs and epigenetic mechanisms, and further discuss pharmacological approaches that modulate epigenetic effects in the setting of allo-HSCT. .

Keywords: GVHD; IFN- γ; alloreactive T cells; epigenetic regulation; type I interferon. V体育安卓版.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

V体育安卓版 - Figures

Figure 1
Figure 1
Role of type I IFNs and IFN-γ in the development of acute graft-versus-host-disease. Acute graft-versus-host disease (GVHD) is often initiated with the destruction of the epithelial barrier through the conditioning regimens including irradiation and chemotherapy. The signal of pathogen-associated molecular patterns (PAMP) and damage-associated molecular patterns (DAMP) released from damaged cells and microbiota induce the activation of antigen-presenting cells (APCs). Consequently, the production of IFNs by APCs interact with the alloreactive T cells and regulate their activation, differentiation, function and contraction. The proliferation of Th1 cells and effector CD8 T cells result in increased secretion of IFN-γ. The induction of activated alloreactive T cells and cytokines further affect the resident APCs and host tissues contributing to extensive functional incapability and damages of different organs. The IFNs play a critical role in orchestrating T cell activities throughout the induction and effector phase of GVHD. The blue and red dots indicate the IFNs (type I IFNs and IFN-γ, respectively) secreted by adjacent cells. CXCR, CXC chemokine receptors; GI, gastrointestinal; Th, T helper cells; iTreg, induced regulatory T cells; Teff, effector T cell; Teff, memory T cell.
Figure 2
Figure 2
Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways and the epigenetic regulations of IFN signaling in T cell. Generally, the binding of type I IFN to the receptor initiates the engagement of IFNAR1 associated Tyk2 protein tyrosine kinase and the IFNAR2 associated JAK1 protein tyrosine kinase. The signal further passes to the phosphorylation and the heterodimerize of STAT1 and STAT2, which together with IRF9 form the ISGF3 complex in the cytoplasm. ISGF3 translocates into the nucleus and binds to IFN-stimulated response elements (ISREs) found in most of IFN-stimulated genes (ISGs). Alternatively, STAT3 and STAT5 heterodimer are also observed after IFNAR activation in the absence of STAT1. Canonical IFN-γ signaling occurs through IFNGR and activates the JAK1/2 kinases, which further induce the phosphorylation of STAT1. The STAT1 homodimer can directly move into the nucleus and binds to gamma-activated sequence (GAS) sites. The activation of T-cell receptor could also help the co-localization of STAT1 to IFNGR-rich regions of the membrane. The transcription of the downstream genes as well as the production of IFN-γ are tightly regulated by numerous epigenetic enzymes, which control the modification of the DNA and histones. These regulators critically control the T cell activities in the process of GVHD, which allows for possible therapeutic interventions. JAK, Janus kinase; STAT, signal transducer and activator of transcription; IFNAR, interferon alpha receptor; IFNGR, interferon gamma receptor; ISREs, IFN-stimulated response elements; GAS, gamma-activated sequence; TCR, T cell receptor; MHC, major histocompatibility complex; IRF, interferon regulatory factor; HDAC, histone deacetylase; SIRT, sirtuin.
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